Abstract
Overprediction is a major limitation of current crystal structure prediction (CSP) methods. It is difficult to determine whether computer-predicted polymorphic structures are artefacts of the calculation model or are polymorphs that have not yet been found. Here, we reported the well-known vitamin nicotinamide (NIC) to be a highly polymorphic compound with nine solved single-crystal structures determined by performing melt crystallization. A CSP calculation successfully identifies all six Z′ = 1 and 2 experimental structures, five of which defy 66 years of attempts at being explored using solution crystallization. Our study demonstrates that when combined with our strategy for cultivating single crystals from melt microdroplets, melt crystallization has turned out to be an efficient tool for exploring polymorphic landscapes to better understand polymorphic crystallization and to more effectively test the accuracy of theoretical predictions, especially in regions inaccessible by solution crystallization.
Highlights
Overprediction is a major limitation of current crystal structure prediction (CSP) methods
Single crystals of the nine polymorphs were grown from melt microdroplets, and all crystal structures were successfully determined by single-crystal X-ray diffraction (SCXRD)
All six experimental structures with one or two molecules in the asymmetric unit (Z′ = 1 and 2) were found in the lattice energy landscape calculated by crystal structure prediction (CSP)
Summary
Overprediction is a major limitation of current crystal structure prediction (CSP) methods. We reported the well-known vitamin nicotinamide (NIC) to be a highly polymorphic compound with nine solved single-crystal structures determined by performing melt crystallization. We recently reported a general method to cultivate single crystals from a supercooled melt, helping to solve single-crystal structures of melt-crystallized polymorphs[17] This progress will facilitate the elucidation of additional polymorphic structures of organic compounds that escape solution crystallization. All six experimental structures with one or two molecules in the asymmetric unit (Z′ = 1 and 2) were found in the lattice energy landscape calculated by crystal structure prediction (CSP) These findings indicate the potential for melt crystallization to find hidden polymorphs and the prospect of a convergence between experiment and theory
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